CN1098120C - microemulsion - Google Patents

Abstract

The present invention relates to a microemulsion comprising (1) one or two selected from decaglycerol stearate having an HLB of 14 or greater and sucrose stearate having an HLB of 18 or greater, (2) one or two selected from decaglycerol myristate having an HLB of 13 or greater and decaglycerol laurate having an HLB of 14 or greater, (3) a fat-soluble component, and (4) a water-soluble polyol, wherein the weight ratio of (1) to (2) is 1:0.5-1:6.

Description

microemulsion

technical field

The present invention relates to a kind of microemulsion containing fat-soluble components, more specifically, to a kind of microemulsion containing fat-soluble components used in pharmacy, food and cosmetic fields, the particles of the microemulsion The diameter is very small and it is stable in aqueous solution.

technical background

Generally speaking, the smaller the particle size of emulsions, the higher their stability in aqueous solution. It is well known that by adding polyhydric alcohol to the mixture of dissolved oil phase and nonionic surfactant, emulsification can obtain emulsion of fine particle size (Japanese Patent Publication (Kokai) 62-250941, Japanese Patent Publication (Kokoku) 63 -61050, Japanese Patent Laid-Open (Kokai) 63-107740). However, the particle diameters of emulsions obtained by these methods are not small enough, and therefore, it is difficult to maintain stability in low-viscosity aqueous solutions. Another way to reduce particle size is to use a high-pressure homogenizer, which applies strong mechanical action to the emulsion. But this requires additional equipment, greatly increasing the cost of the method. Furthermore, although the emulsions thus obtained are relatively stable in aqueous solutions with neutral pH and low ionic concentration, they are, however, unstable in aqueous solutions at pH 2.5-5.0, which are often used in medicinal beverages , cool drinks, etc., are also unstable in aqueous solutions containing inorganic salts, organic acid salts, etc., and the concentration of ionic substances in this aqueous solution is as high as 0.1-5% (weight), so it is easy to form water slurry or precipitation.

The invention is disclosed

An object of the present invention is to provide a microemulsion containing fat-soluble components, the particle size is very small, 200nm or less, in aqueous solution, especially at pH 2.5-5.0 or ionic substance weight It can be stable for a long time in an aqueous solution with a concentration as high as 0.1-5%.

In order to achieve the above object, after long-term research, the inventor found that by mixing specific nonionic surfactants in a specific ratio, a microemulsion with a particle size of 10-150 nm can be obtained, even at a pH of 2.5-5.0 An aqueous solution or an aqueous solution with a high ion concentration of 0.1-5% by weight of the ion substance can be very stable for a long time, thereby completing the present invention.

Therefore, the microemulsion of the present invention comprises (1) one or two kinds selected from decaglycerol stearate with HLB of 14 or greater and sucrose stearate with HLB of 18 or greater , (2) one or two kinds selected from the group consisting of decaglyceryl myristate with an HLB of 13 or greater and decaglyceryl laurate with an HLB of 14 or greater, (3) fat-soluble components, and ( 4) Water-soluble polyol, wherein the weight ratio of (1) and (2) is 1:0.5-1:6.

The present invention is characterized in that specific surfactants are mixed in specific ratios to obtain microemulsions with a particle diameter of 200 nm or less even in an aqueous solution with a pH of 2.5-5.0 or an ionic substance weight concentration of 0.1-5% It can be very stable for a long time in an aqueous solution with high ion concentration.

In order to ensure the stability of droplet-like microemulsions in low-viscosity aqueous solutions, it is necessary to reduce the particle size to 200 nm or less. In particular, the particle diameter is preferably 10-150 nm.

The decaglyceryl stearate, nonionic surfactant used in the present invention has an HLB value of 14 or greater, preferably 15 or greater. The HLB value of decaglyceryl stearate being 14 or more means that the content of monostearate in decaglyceryl stearate is 45% or more. Sucrose stearate is an ester of stearic acid and sucrose, and the HLB value of sucrose stearate is 18 or greater, preferably 19 or greater. The HLB value of sucrose stearate of 18 or more means that the content of monostearate in sucrose stearate is 90% or more. The HLB value of decaglyceryl myristate is 13 or greater, preferably 14 or greater, and the HLB value of decaglyceryl myristate is 13 or greater means that the monoglyceryl myristate The content of myristate is 45% or greater. The HLB value of decaglyceryl laurate is 14 or more, preferably 15 or more, and the HLB value of decaglyceryl laurate is 14 or more means that the monolaurate in decaglyceryl laurate Content is 45% or greater.

Therefore, in the decaglyceryl stearate, sucrose stearyl ester, decaglyceryl myristate and decaglyceryl laurate used in the present invention, the content of monoester is greater than a certain value, can use 100% pure monoester.

One or both of decaglycerol stearate (decaglycerol) with HLB of 14 or greater and sucrose stearate with HLB of 18 or greater and meat selected from meat with HLB of 13 or greater The weight ratio of one or both of decaglyceryl myristate and HLB in decaglycerol laurate of 14 or greater is 1:0.5-1:6, preferably 1:0.6-1:5, further Preferably it is 1:0.7-1:4.

Even nonionic surfactants with an HLB of 12 or greater cannot produce microemulsions with particle sizes below 200 nm unless the specific mixtures described above are used. In other words, even if such a microemulsion is obtained, its stability cannot be guaranteed at low temperature (5°C).

The fat-soluble components used in the present invention include fat-soluble vitamins, such as vitamins A, D, E, F, K and U, carotenoids, their derivatives, and fat-soluble drugs, such as γ-oryzanol and the like. Among them, vitamin D (such as vitamin D ₂ , vitamin D ₃ , active vitamin D, and metabolites and derivatives thereof) and vitamin E are particularly effective.

Further, the fat-soluble components used in the present invention can be added with various oily substances, including vegetable or animal oils, such as avocado oil, camellia oil, turtle oil, walnut oil, corn oil, mink oil, olive oil, rapeseed oil , egg butter, sesame oil, wheat germ oil, camellia oil, pyrene sesame oil, safflower oil, cottonseed oil, soybean oil, peanut, cocoa butter, lanolin, medium-chain fatty acid triglycerides, such as tricapric glycerin, tricaprylic glycerin ester.

The weight ratio of nonionic surfactant to fat-soluble components (or the total amount of fat-soluble components and oily substances) is usually 1: 0.1-1: 3, preferably 1: 0.4-1: 3, more preferably 1 : 0.2-1: 2. When the ratio of the fat-soluble component to the nonionic surfactant exceeds 3, a microemulsion having a particle diameter of 200 nm or less cannot be obtained.

Examples of water-soluble polyhydric alcohols include ethylene glycol, propylene glycol, 1,3-butanediol, 1,4-butanediol, dipropanol, polypropylene alcohol, glycerin, diglycerin, polyglycerol, erythritol, wood Sugar alcohols, sorbitol, maltitol, lactitol, mannitol, trehalose, sugar alcohols derived from starch digestion products, etc. Among these water-soluble polyols, glycerin, diglycerol, polyglycerol and sorbitol are particularly preferable, and these polyols are generally used in the form of aqueous products when preparing the emulsion of the present invention. At this time, the weight ratio of the water-soluble polyol to water is preferably 95:5-50:50, particularly preferably 90:10-55:45.

The weight ratio that is used for fat-soluble component of the present invention and nonionic surfactant total amount to water-soluble polyalcohol hydrous product (water-soluble polyhydric and water mixture) is preferably 1: 0.05-1: 10, particularly preferably 1: 0.1-1:8.

When 85% glycerin aqueous solution was used as water-soluble polyhydric alcohol, the weight ratio of 85% glycerol aqueous solution to nonionic surfactant total amount was preferably 1: .05-1: 1.45, and 85% glycerol aqueous solution to fat-soluble The weight ratio of the fraction (or the total amount of the fat-soluble component and the oily substance) is preferably 1:0.37-1:3.7.

The microemulsions of the present invention containing fat-soluble components can be prepared by conventional methods for obtaining emulsions. Therefore, one or both of the above decaglyceryl stearate and the above sucrose stearate, one or both of the above decaglyceryl myristate and the above decaglyceryl laurate , and the fat-soluble components are mixed, optionally heated, and the insoluble polyol is then added in portions with stirring to obtain the microemulsion containing the fat-soluble components of the present invention.

The thus obtained microemulsions containing fat-soluble components are diluted in appropriate water and used in the fields of pharmacy, food, cosmetics and the like. In this case, the dilution factor is typically 10-100000, but not limited thereto.

The particle size of the microemulsion diluted in water is 20nm or smaller, and it can be very stable for a long time in an aqueous solution with a pH of 2.5-5.0 or an aqueous solution with a high ion concentration of 0.1-5% by weight of ionic substances .

An ionic substance used in the present invention is a substance that forms ions in an aqueous solution. For example, they are inorganic salts such as sodium chloride, potassium chloride, magnesium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, and organic acids such as citric acid, malic acid, grape acid, tartaric acid , fumaric acid, succinic acid, lactic acid, ascorbic acid, erysorbic acid, aspartic acid, alkali metal salts (such as sodium or potassium salts) or alkaline earth metal salts (such as calcium or magnesium salts), which One or more of the above may be included.

When the microemulsion containing fat-soluble components of the present invention is used for pharmaceuticals, other components which do not affect the present invention may be blended. For example, they are water-soluble vitamins such as vitamins B ₁ , B ₂ , B ₆ , B ₁₂ , and vitamin C, vitamin B ₅ , niacin, vitamin H, chloride of carnitine, their salts and their derivatives , taurine, muscle sugar, sodium chondroitin sulfate, caffeine, crude drug extracts, etc. Sweeteners, pH regulators, preservatives, spices, colorants, thickeners, chelating agents, ethanol, etc. can be added. Sweeteners include, for example, sucrose, lactose, fructose, glucose, sorbitol, maltitol, erythritol, xylitol, trehalose, lactitol, any plant extracts of this genus or related ones, and the like. pH adjusters include, for example, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and salts thereof. Preservatives include, for example, parabens, such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben, benzoic acid, and salts thereof. Flavors include, for example, fruit flavors such as orange, grape fruit, apple, lemon, lime, tangerine, Chinese lemon, citrus quince, citrus natsudaidai, grape, strawberry, pineapple, banana, peach, Various melons, watermelons, plums, cherries, pears, apricots, red currants, Japanese apricots, mangoes, pomegranates, raspberries and bilberries, black tea, green tea, cocoa, chocolate, coffee, almonds, maple, vanilla, whiskey, brandy , ram, red wine, various wines, cocktails, mint, etc., they can be used alone or in a mixed flavor of two or more.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

The particle diameters described here are average particle diameters measured using a dynamic light scattering method, particularly measured with a NICOMP370 model (manufactured by HIAC/ROYCO).

Example 1

(1) Tocopheryl acetate 50g

(2) Decaclyceryl myristate (HLB14) 25g

(3) Sucrose stearate (HLB19) 8g

(4) 70% glycerin aqueous solution 50g

(1), (2) and (3) were mixed at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (4) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 90nm.

Example 2

(1) Tocopheryl acetate 50g

(2) Decaclyceryl myristate (HLB14) 15g

(3) Ten polyglyceryl stearate (HLB15) 15g

(4) 80% aqueous glycerin solution 30g

(1), (2) and (3) were mixed at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (4) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 60nm.

Example 3

(1) Tocopheryl acetate 50g

(2) Decaclyceryl Laurate (HLB15.5) 15g

(3) Decaclyceryl myristate (HLB14) 15g

(4) Ten polyglyceryl stearate (HLB15) 15g

(5) Sucrose stearate (HLB19) 8g

(6) 70% aqueous glycerin solution 70g

Mix (1), (2), (3), (4), (5) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (6) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 110nm.

Example 4

(1) Retinyl Acetate 1g

(2) Tocopherol 5g

(3) Vitamin D ₃ 1g

(4) Soybean oil 20g

(5) Tricapric Glycerin 10g

(6) Decaclyceryl Laurate (HLB15.5) 9g

(7) Decaclyceryl myristate (HLB14) 21g

(8) Sucrose stearate (HLB19) 8g

(9) 85% propylene glycol oil solution 100g

Mix (1), (2), (3), (4), (5), (6), (7), (8) at 60-70°C. Thereafter, the mixture was brought back to room temperature and (9) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 130nm.

Example 5

(1) Tocopheryl acetate 50g

(2) γ-Oryzanol 5g

(3) Decaclyceryl myristate (HLB14) 12g

(4) Ten polyglyceryl stearate (HLB15) 16g

(5) 80% aqueous glycerin solution 40g

Mix (1), (2), (3), (4) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (5) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 80nm.

Example 6

(1) Beta-carotene 5g

(2) Tocopherol 5g

(3) Vitamin D ₃ 1g

(4) Olive oil 10g

(5) Tricaprylic Glycerin 10g

(6) Decaclyceryl Laurate (HLB15.5) 3g

(7) Decaclyceryl myristate (HLB14) 10g

(8) Ten polyglyceryl stearate (HLB15) 13g

(9) Sucrose stearate (HLB19) 5g

(10) 65% aqueous glycerin solution 75g

(1), (2), (3), (4), (5), (6), (7), (8) and (9) were mixed at 60-70°C. After this time, the mixture was brought back to room temperature and (10) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 105nm. Comparative example 1

(1) Tocopheryl acetate 50g

(2) Decaclyceryl myristate (HLB14) 50g

(3) 70% glycerin aqueous solution 50g

Mix (1), (2) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (3) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 270nm. Comparative example 2

(1) Tocopheryl acetate 50g

(2) Sucrose stearate (HLB12) 50g

(3) 70% glycerin aqueous solution 50g

Mix (1), (2) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (3) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 350nm. Comparative example 3

(1) Tocopheryl acetate 50g

(2) Sucrose stearate (HLB19) 50g

(3) 70% glycerin aqueous solution 50g

Mix (1), (2) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (3) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 400nm. Comparative example 4

(1) Tocopheryl acetate 50g

(2) γ-Oryzanol 5g

(3) Decaclyceryl myristate (HLB14) 7g

(4) Sucrose stearate (HLB19) 50g

(5) 70% sorbitol aqueous solution 80g

Mix (1), (2), (3), (4) at 60-70°C. Thereafter, the mixture was brought back to room temperature, and (5) was added in several portions to obtain a gel. Dilute the product 50 times with pure water to obtain a uniform microemulsion with a particle size of 410nm. Test case

The following tests were carried out for comparing the microemulsions obtained in Examples with the emulsions obtained in Comparative Examples. The pH was adjusted to the range of 2.5-6.0 by adding 1 N aqueous NaOH to 0.1% aqueous malic acid. These samples were placed in 5ml ampoules and the ampoules were sealed. The changes in the characteristics of the emulsion were then observed at 5°C and 40°C. The results are listed in Tables 1 and 2.

The microemulsions containing fat-soluble components of Examples 1-6 have better stability at low pH and high ion concentration than the emulsions of Comparative Examples 1-4.

The pH of the aqueous solution of Table 1 and the stability (characteristic) of the emulsion Example comparative example 1 2 3 4 5 6 1 2 3 4 pH2.55℃ pH4.01 month pH5.0pH6.0 ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○ ○○ ○ ○ pH2.55℃ pH4.06 months pH5.0pH6.0 ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○     pH2.540℃ pH4.01 month pH5.0pH6.0 ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ×▲▲▲ ▲▲▲▲ ××▲▲ ××▲▲ pH2.540℃ pH4.06 months pH5.0pH6.0 ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ×××× ×××× ×××× ×××▲

○: No change, : Stratification, ▲: Precipitation, ×: Complete separation

The concentration of the brine of table 2 aqueous solution and the stability (characteristic) of emulsion Example comparative example 1 2 3 4 5 6 1 2 3 4 0.1% 5℃ 0.5% 1 month 1.0% 5.0% ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○ ○○ ○ ○ 0.1% 5℃ 0.5% 6 months 1.0% 5.0% ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○     0.1% 40℃ 0.5% 1 month 1.0% 5.0% ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○▲▲× ○○▲▲ ○▲▲▲ ○▲▲× 0.1% 40℃ 0.5% 6 months 1.0% 5.0% ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ○○○○ ×××× ▲▲×× ▲▲×× ▲▲××

○: No change, : Stratification, ▲: Precipitation, ×: Complete separation

Industrial Applicability

The microemulsions of the present invention have very small particle sizes, 200 nm or less, and are stable for long periods of time when diluted in water. Further, the microemulsion of the present invention is very stable in an aqueous solution with a pH of 2.5-5.0 or an aqueous solution with a high ion concentration of 0.1-5% by weight of ionic substances. In the past, it was generally believed that it was difficult to ensure emulsification under such conditions liquid stability. Therefore, the microemulsion containing fat-soluble components of the present invention can be widely used in the fields of pharmacy, food and cosmetics.

Claims (5)

1. microemulsion comprises:

(1) one or both be selected from HLB be 14 or bigger stearic acid ten polyglycerol esters and HLB be 18 or bigger stearic acid sucrose ester,

(2) one or both be selected from HLB be 13 or bigger myristic acid ten polyglycerol esters and HLB be 14 or bigger laurate ten polyglycerol esters,

(3) fat-soluble ingredient and

(4) water-soluble polyol,

Wherein, the weight rate of (1) and (2) is 1: 0.5-1: 6.

2. the microemulsion of claim 1, wherein water-soluble polyol uses with the form of water-containing products, and water-soluble polyol is 95 to the weight ratio of water: 5-50: 50.

3. the microemulsion of claim 1, wherein the total amount of (1) and (2) is 1 to the weight rate of fat-soluble ingredient (3): 0.1-1: 3.

4. the microemulsion of claim 1, its particle diameter is 200nm or littler.

5. the microemulsion of claim 1 is to be very stable in the aqueous solution of 2.5-5.0 or the aqueous solution of ionic species weight concentration up to 0.1-5% at pH.